The survival impact of concurrent chemotherapy and primary tumor radiotherapy on stage IV squamous non-small-cell lung cancer Yichao Geng The First Clinical Medical College of Lanzhou University,Lanzhou 730000,Gansu Qiu-Ning Zhang Gansu Provincial Cancer Hospital Yin-Xiang Hu Department of Thoracic Oncology,Aliated Hospital of Guizhou Medical University,and Guizhou Cancer Hospital Zhu Ma Department of Thoracic Oncology,Aliated Hospital of Guizhou Medical University, and Guizhou cancer Hospital Wei-Wei Ouyang Department of Thoracic Oncology,Aliated Hospital of Guizhou Medical University,and Guizhou Cancer Hospital Sheng-Fa Su Department of Thoracic Oncology,Aliated Hospital of Guizhou Medical University,and Guizhou Cancer Hospital Qing-Song Li Department of Thoracic Oncology,Aliated Hospital of Guizhou Medical University,and Guizhou Cancer Hospital Hui-qin Li Department of Thoracic Oncology,Aliated Hospital of Guizhou Medical University,and Guizhou Cancer Hospital Xiaohu Wang ( [email protected] ) Bing Lu Department of Thoracic Oncology,Aliated Hospital of Guizhou Medical University,and Guizhou Cancer Hospital Ruifeng Liu Gansu Provincial Cancer Hospital Hongtao Luo Gansu Provincial Cancer Hospital Shihong Wei Page 1/17 Gansu Provincial Cancer Hospital Lina Wang The First Clinical Medical College of Lanzhou University,Lanzhou 730000,Gansu Research article Keywords: Stage IV; Squamous non-small cell lung cancer (NSCLC); Concurrent chemoradiotherapy; Overall survival Posted Date: October 15th, 2019 DOI: https://doi.org/10.21203/rs.2.16077/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 2/17 Abstract Objective: To analyse the impact of survival with three-dimensional radiotherapy for stage IV squamous non-small cell lung cancer (NSCLC). Methods: Data for 629 eligible patients who received three-dimensional radiotherapy between 2002 and 2016 were retrospectively analyzed.161 of 183 cases were included pre-protocol. Patients received platinum-doublet chemotherapy with concurrent irradiation of the primary tumour. Primary endpoints were overall survival (OS) and progress-free survival (PFS). Results: Of 161 patients, the 1-, 2-, 3- and 5-year OS rates and median survival time (MST) were 45.7%, 14.1%, 11.2%, 2.2% and 11months, respectively. Using contrastive analysis PTV dose ≥63 Gy and <63 Gy, the 1-, 2-,3- and 5-year overall survival (OS) rates and median survival time (MST)were 48.9% vs 43.3%, 21.8% vs 8.2%, 18.4% vs 4.4%, 5.1% vs 0%, and 12 months vs 11months ( χ 2 = 7.222, P=0.007). Contrastive analysis patients received radical concurrent chemoradiation therapy, and the 1-, 2-, 3- and 5- year overall survival (OS) rates and median survival time (MST) were 54.3% vs. 37.2%, 27.2% vs. 7.5%, 24.9% vs. 4.8%, 8.3% vs. 0%, and 14 months vs. 10 months ( χ 2 = 13.180, P=0.000). Multivariate analysis showed that PTV ≥63 Gy was an independent favourable factor for survival. Conclusion: Concurrent chemotherapy and three-dimensional radiotherapy to the primary tumour in stage IV squamous NSCLC could prolong survival, and with increasing intensity of comprehensive treatment, OS gradually improved. PTV ≥63 Gy is the independent prognostic factors for OS. [Key Words] Stage IV; Squamous non-small cell lung cancer (NSCLC); Concurrent chemoradiotherapy; Overall survival Background At present, lung cancer is still the leading cause of cancer deaths worldwide[1]. Non-small cell lung cancer(NSCLC) accounts for approximately 75% of the cancers and consists of squamous cell, adenocarcinoma and other cell types. Squamous cell carcinomas account for 30% of NSCLC worldwide[2]. The majority of lung cancers (57%) are diagnosed at a distant stage, and the 5-year survival rate is approximately 4% for distant stage disease. In recent years, rst-line chemotherapy, including third- generation agents (including gemcitabine, paclitaxel, and pemetrexed), molecular targeted therapies or immunotherapy drugs, has improved overall survival (OS) of patients with advanced NSCLC[1, 3, 4]. For patients with non-squamous NSCLC without identied oncogenic drivers, bevacizumab, a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF), in combination with platinum-based chemotherapy, remains a valid rst-line treatment option[5-8]. Cisplatin or carboplatin combined with pemetrexed and concurrent radiation therapy may also associated with more clinical benets[9, 10]. However, none of the above treatments are suitable for patients with squamous NSCLC. The discovery of activating mutations of the epidermal growth factor receptor (EGFR) and the echinoderm microtubule-associated protein-like 4–anaplastic lymphoma kinase (EML4-ALK) fusion has led to changing treatments for patients with NSCLC who harbour these drivers. Agents that inhibit the tyrosine kinase binding sites of these molecules have demonstrated improved PFS versus chemotherapy [11-13]. However, these mutations are very rare in squamous NSCLC [2, 14]. Page 3/17 For patients with squamous NSCLC, although some potentially targetable molecular lesions have been identied in tumours[2], including PIK3CA amplication, FGFR1 amplication, MET amplication, and DDR2 mutation, none of these biomarkers have yet been validated in this setting as predictive for targeted therapies, and available rst-line regimens have remained essentially unchanged for the past two decades. In general, such regimens comprise a platinum-based doublet of cisplatin or carboplatin combined with gemcitabine, vinorelbine, or a taxane [2, 15]. ECOG1594 study shows that the third- generation agents combined with platinum had similar ecacy in the treatment of advanced NSCLC.The median survival about 8 months, 1-year OS ~ 30%[4].The treatment with chemotherapy alone entered a plateau.Thus, new strategies involving combinations of chemotherapy with other treatment modalities should be explored. Some studies have shown that controlling the primary tumour may be important in prolonging survival among patients with advanced NSCLC. Local control of the primary tumour has not only reduced symptoms but also improved overall survival (OS) [16, 17]. More evidence suggests that some patients with stage IV disease could benet from aggressive thoracic radiation therapy beyond palliative irradiation [18-20]. Moreover, the role of concurrent chemotherapy with thoracic radiation therapy for advanced NSCLC is not well-dened [19, 21]. Our previous study showed that treatment of IV NSCLC with joint administration of four to ve cycles of chemotherapy and three-dimensional radiotherapy may prolong survival especially for patients with single metastatic sites [22-24]. However, the role of chemotherapy given concurrently with primary tumor radiotherapy for stage IV squamous NSCLC patients is not well-dened, and the independent prognostic factors for OS in stage IV squamous NSCLC patients treated with concurrent chemoradiotherapy remains to be answered. Therefore, 164 eligible stage IV squamous NSCLC patients come from multiple cancer centers and tumor hospitals who received three- dimensional radiotherapy between 2002 and 2016 were retrospectively analyzedwe assessed the impact of survival with primary tumour radiotherapy and concurrent chemotherapy for stage IV squamous NSCLC patients. Methods Patient selection Inclusion criteria of patients are as follows: (1) Histologically or cytologically conrmed Squamous Carcinoma; (2) Newly diagnosed stage IV disease (staged according to the 2002 system of the American Joint Committee on Cancer); (3) No previous anticancer treatment; (4) 18 to 80 years of age; (5) Karnofsky performance status (KPS) score ≥ 70; (6) No contraindications to radiation therapy or chemotherapy; (7) Metastatic disease limited to ≤3 organs; and (8) Presumed ability to tolerate thoracic radiation therapy at a dose of ≥36 Gy in 20 fractions. Exclusion criteria were (1) a history of thoracic surgery, radiation therapy, or chemotherapy; (2) pregnancy or lactation at the time of enrolment; (3) previous malignancy or other concomitant malignant diseases. Page 4/17 Pre-treatment evaluations All patients underwent brotic bronchoscopy and contrast-enhanced computed tomography (CT) of the chest to evaluate the extent of the primary tumour and regional lymph node status. All patients also underwent bone scintigraphy, contrast-enhanced CT of the abdominal region, and magnetic resonance imaging (MRI) of the head to detect distant metastases. Positive ndings on positron emission tomography (PET)/CT or bone scintigraphy required additional radiologic conrmation (e.g., MRI or CT of the bone). Pre-treatment evaluations were completed within 2 weeks before treatment started. Thoracic radiotherapy protocol All patients were immobilized in the supine position using a T bar, wing board, and Vac-lock cradle. Images with contrast were obtained from the CT simulator for treatment planning purposes. All patients were scanned using serial 5-mm slices from the hyoid bone through the third lumbar vertebra. All patient 3D-CRT or IMRT treatment plans were performed using the ADAC pinnacle planning system (version 7.4f), and dose distribution was computed with a tissue heterogeneity correction. Chemotherapy protocol Platinum-based doublets chemotherapy(cisplatin in combination with docetaxel, paclitaxel or vinorelbine) was used for all patients, and concurrent thoracic radiation was given within 1 week following the start of chemotherapy. The commonly used regimens were as follows: